The invention concerns N-substituted 2-chloro-7-fluoro-10-piperazino-10, 11-dihydrodibenzo (b,f) thiepins of the general formula I ##STR2## in which R represents an aminocarbonyl, amino-oximinomethyl (amidoxime), 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl group, and their addition salts with pharmaceutically acceptable organic and inorganic acids.
The compounds of the invention are highly potent antidopaminergic, non-cataleptic neuroleptic agents useful for the treatment of schizophrenia. According to recent pharmacological assay results, the compounds are surprisingly of low-toxicity and are expected to be substantially free of the common undesired extrapyramidal side effects (i.e. lowered motor coordination and related disturbances). Their acid addition salts, e.g. hydrochlorides, maleates and especially methanesulfonates, can be used in the formulation of dosage forms for pharmacological evaluation and therapeutic application.
The basic 10,11-dihydrodibenzo (b, f) thiepin skeleton of the compounds of formula I is a well-known carrier system for a number of neuroleptic substances from which several have found practical use in pharmacotherapy of schizophrenia, e.g. clorotepin (8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo (b,f) thiepin, Metysova J. et al, Acta Biol. Med. Ger. 39, 723, 1980), oxyprothepin (8-methylthio-10-(4-(3-hydroxypropyl) piperazino)-10, 11-dihydrodibenzo (b,f)-thiepin, Taussigova D. et al, Activ. Nerv. Supper. 16, 163, 1974), oxyprothepin decanoate (8-methylthio-10-(4-(3-decanoyloxypropyl)-piperazino)-10,11-dihydrodibenzo (b,f) thiepin, Zapletalek M. et al, Activ. Nerv. Super. 21, 138, 1979) and zotepin (2-chloro-11-(2-dimethylaminoethoxy)dibenzo (b,f) thiepin, Uchida S et al, Arzneim.-Forsch. 29, 1588, 1979).
Common disadvantages of all these compounds are their cataleptic action in rats and the corresponding extrapyramidal side effects in patients. The typical structural feature of the compounds of formula I, which evidently modifies their pharmacological profile in the desired direction, is the N-substituent --CH.sub.2 CH.sub.2 R on the piperazine N.sup.4. The relevant literature (Jilek J. O. et al, Collect. Czech. Chem. Commun. 36, 2226, 1971; 39, 3153, 1974; Rajsner M. et al, ibid. 42, 3079, 1977) describes only several compounds of the general formula II ##STR3## wherein R has the same meansing as in formula I and R.sup.1 is a hydrogen or a fluorine atom. All these compounds, some of which differ from those of formula I merely by the position of the chlorine and fluorine atoms on the tricyclic skeleton, are also very potent neuroleptic agents, but simultaneously cause a significant cataleptic activity and, consequently, elicit extra-pyramidal side effects in patients. One can only conclude that the noncataleptic character of the compounds of formula I, together with their high antidopaminergic activity in biochemical and pharmacological tests (cf. Sayed Y. and garrison J. M., Psychopharmacol. Bull. 19 (2), 283-288, 1983, "The dopamine hypothesis of schizophrenia and the antagonistic action of neuroleptic drugs--a review"), results from the specific location of the halogen (i.e. chlorine and fluorine) atoms on the skeleton, in combination with the particular structure of the piperazine N.sup.4 substituent.